PubMed · 8303673
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
P T Turkington. 1993-11-15. Cathepsin G activates human factor V in vitro.. https://doi.org/10.1016/0049-3848(93)90142-b
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
The CXC chemokines platelet factor 4 (PF-4/CXCL4) and connective tissue-activating peptide III (CTAP-III) are released by activated human platelets in micromolar concentrations. So far, neutrophils have been recognized to cleave the precursor CTAP-III to form the active chemokine neutrophil-activating peptide 2 (NAP-2/CXCL7) through limited proteolysis by membrane-associated cathepsin G. Here we show for the first time that activated human skin mast cells (MCs) convert CTAP-III into biologically active NAP-2 through proteolytic cleavage by released chymase. A direct comparison on a cell number basis revealed that unstimulated MCs exceed the CTAP-III-processing potency of neutrophils about 30-fold, whereas MCs activated by IgE cross-linking exhibit even 1000-fold higher CTAP-III-processing capacity than fMLP-stimulated neutrophils. Intriguingly, PF-4 counteracted MC- as well as neutrophil-mediated NAP-2 generation at physiologically relevant concentrations. Addressing the underlying mechanism, we obtained evidence that PF-4 acts as an inhibitor of the CTAP-III-processing enzymes cathepsin G and chymase without becoming cleaved itself as a competitive substrate. Because cleavage of the CTAP-III-unrelated substrate substance P was also affected by PF-4, our results suggest a regulatory role for PF-4 not only in NAP-2 generation but also in neutrophil- and MC-mediated processing of other physiologically relevant inflammatory mediators.
The mechanism of initiation and growth of a thrombus in atherosclerotic arteries, although investigated extensively, has not been sufficiently elucidated. Understanding the molecular mechanisms that lead to stroke, unstable angina and myocardial infarction is of paramount importance. Protease-activated receptors (PARs) belong to a recently discovered and so far not fully characterized family of transmembrane proteins, which are involved in the initiation growth of thrombi in atherosclerotic arteries. PARs are a G-protein-coupled family of receptors which mediate a cellular function with the aid of enzymes. All of them have identical structural organization and are activated by a very similar mechanism. The enzyme (serine protease) cleaves an extracellular amino-terminal fragment of the receptor in order to unmask a new amino-terminal, 5-6 residues of which serve as the tethering ligand, able to activate its maternal receptor. According to the most recently published reports, in eukaryotic organisms there are 5 different PARs: from PAR 1 to PAR 4 found in human organisms and PAR 5 discovered as a 14-3-3 protein, identified firstly in C. elegans and Drosophila melanogaster. Up to now numerous experiments have been conducted with the aim to understand more precisely the mechanisms of PARs activation and activity. The present paper summarizes the most important and most recently published reports concerning this problem, which seems to be most relevant in angiology.
The antimicrobial and proinflammatory neutrophil granule protein cathepsin G (CaG) has been reported as a chemoattractant for human phagocytic leukocytes by using a putative G protein coupled receptor. In an effort to identify potential CaG receptor(s), we found that CaG-induced phagocyte migration was specifically attenuated by the bacterial chemotactic peptide fMLP, suggesting these two chemoattractants might share a receptor. In fact, CaG chemoattracts rat basophilic leukemia cells (RBL cells) expressing the high affinity human fMLP receptor FPR, but not parental RBL cells or cells transfected with other chemoattractant receptors. In addition, a specific FPR Ab and a defined FPR antagonist, cyclosporin H, abolished the chemotactic response of phagocytes and FPR-transfected cells to CaG. Furthermore, CaG down-regulated the cell surface expression of FPR in association with receptor internalization. Unlike fMLP, CaG did not induce potent Ca(2+) flux and was a relatively weaker activator of MAPKs through FPR. Yet CaG activated an atypical protein kinase C isozyme, protein kinase Czeta, which was essential for FPR to mediate the chemotactic activity of CaG. Thus, our studies identify CaG as a novel, host-derived chemotactic agonist for FPR and expand the functional scope of this receptor in inflammatory and immune responses.